A vaccine is urgently needed to prevent HIV transmission and AIDS in children born to the rapidly increasing number of HIV-infected women throughout the developing world. Any vaccine to prevent AIDS in children must be safe to give at birth and must rapidly elicit virus-specific immunity in the presence of maternal antiviral antibodies to protect against the multiple postnatal exposures to HIV through breast feeding. HIV vaccines currently being evaluated in adults appear to elicit immunity too slowly to prevent postnatal HIV transmission or pediatric AIDS. Thus, studies of the immunogenicity and efficacy of HIV immunogens in human infants are essential to developing an HIV vaccine to prevent pediatric AIDS; however, such studies are extremely technically demanding and ethically challenging. Our proposed project will use the SIV/neonatal rhesus model of pediatric HIV/AIDS to evaluate immunogenicity and efficacy of candidate primate lentiviral vaccines in newborn and infant primates; this model is uniquely suited to provide information needed to develop vaccines against vertical HIV transmission and pediatric AIDS. To determine the host defense responses elicited by two attenuated, recombinant poxvirus-based SIV vaccines (MVA-SIVgpe and ALVAC-SIVgpe) that are necessary to protect infant rhesus macaques against multiple, low dose oral SIV challenge (at 4 weeks of age) we will: 1) Evaluate whether passive transfer of hyper-immune serum from adult macaques immunized with poxvirus-based SIV vaccines can protect infant macaques against infection or disease after oral SIV exposure. 2) Determine whether an SIV-poxvirus vaccine regimen administered to macaques at birth can elicit protective immunity against oral SIV infection or disease rapidly in infants who have, or who lack, passively-acquired SIV- and poxvirus-specific antibodies. 3) Determine if specific immune cell populations (i.e. CD8+ cells, NK cells) are necessary or sufficient for vaccine-mediated protection of infant macaques against oral SIV by selectively depleting cells (with monoclonal antibodies) in vaccinated animals before oral SIV challenge.